The greater Baltimore area in Maryland has a large population of African-Americans and European-Americans, which makes this area most suitable to investigate differences in the exposure to prostate cancer risk factors among these two population groups. We designed a study that will use an integrated molecular epidemiology and translational research approach to examine causes for the excessive burden of prostate cancer among African-American men, including the study of tumor biological differences between African-American and European-American patients, supported by the collection of blood, urine, tissue samples, and survey data. Other epidemiological studies of prostate cancer have been established in recent years; however, only a few of these studies address the need for health disparity research and will have the opportunity to collect fresh-frozen tumor specimens from case subjects. Our study was implemented in two phases. The first phase, which started in April of 2005, constituted a pilot study to evaluate recruitment procedures. This phase was successful and the full study was initiated with minor changes to the protocol in April of 2006. The full study was completed in 2015 [976 cases (489 African-American and 487 European-American) and 1034 population-based controls (486 African-American and 548 European-American)]. We collected blood and urine from all individuals and paraffin-embedded and fresh-frozen tissue specimens form 135 prostatectomy surgeries. Cases are from two Baltimore hospitals, the Veterans Affairs Medical Center and the University of Maryland Medical Center. Cases have pathologically confirmed prostate cancer. They had a disease diagnosis within the last two years prior to recruitment and presented with prostate cancer at all stages of the disease. One-hundred and thirty-eight cases had advanced stage disease (n = 79 with T3 and n = 59 with T4 disease). Furthermore, we defined 823 patients as incident cases (422 African-American, 401 European-American) when they were recruited into the study within one year after the disease diagnosis, having an average interval between diagnosis and enrollment into our study of 4.8 months (4.4 months for African-American and 5.2 months for European-American men). The population-based controls were identified through the Maryland Department of Motor Vehicles database, and were frequency-matched by age and race to cases. The study involved the administration of a survey and collection of blood and urine from all study subjects. Fresh-frozen tumor specimens were obtained from cancer patients if they were available after prostatectomy. Our survey evaluates tobacco use, medication use, occupational history, diet, medical and sexual history, familial cancer history, and socioeconomic status. Current activities in this study include the collection of additional data from pathology and medical records to have clinicopathology for all cases and information on disease recurrence as available. We are also obtaining survival data from the National Death Index. In collaboration with Rick Kittles at the University of Arizona, we typed 864 cases and all controls for ancestry marker to obtain proportions of West African, Caucasian, and Native American ancestry in these men. The analysis of survey data is in ongoing. Our study is aimed at identifying differences in risk factor exposure and tumor biology between African-American and European-American men. We will test the hypothesis that environmental and genetic factors and their interactions contribute to the existing prostate cancer health disparity among African-Americans and European-Americans. Molecular work will be used to examine race/ethnic differences in tumor biology. Our research is also aimed at identifying environmental and inherited factors (e.g., infections and immune response, smoking exposure, ancestry-related factors, low penetrance susceptibility loci) that promote the development of an aggressive disease and specifically contribute to the survival disparity between African-American and European-American men. A major research focus is the role of tumor and systemic inflammation in disease progression because of our previous observation that tumors of African-American patients contain a prominent immune-inflammation gene signature. Additionally, we have been examining the role of cigarette smoking in the development of metastatic prostate cancer with the analysis of human tumors and the use of cell lines and a mouse model of metastatic prostate cancer. Data from this project suggest that the underlying molecular mechanism - a tumor-associated immune-inflammation gene signature - could be a shared risk factor among smokers and men of African descent and promotes disease progression. In a first analysis of our questionnaire data, we investigated the link between the regular use of aspirin and prostate cancer. This study has been completed and made a clinically significant observation. Aspirin use has previously been shown to protect against several cancers but most effectively against colon cancer. Investigations of mainly European or European-American men observed that aspirin use decreases the risk of prostate cancer development and progression; however, the findings across studies were heterogeneous, and the risk reduction by aspirin was generally modest. In contrast, our study shows that aspirin use significantly reduces the risk of aggressive prostate cancer in African-American men. Moreover, regular aspirin use significantly reduced disease recurrence in these men. We did not find the same protective effects of aspirin among the European-American men. Thus, regular aspirin use before and after a prostate cancer diagnosis may prevent the development of an aggressive disease in African-American men who are at high risk of a lethal malignancy. This finding has been corroborated with an analysis of the Southern Community Cohort Study (SCCS). Here, we found that regular aspirin use protects against prostate cancer mortality among the African-American men in SCCS (manuscript submitted). In another study, we explored potential differences in the association of body fatness with prostate cancer between African-American and European-American men. The anthropometric measures that assessed body fatness included body mass index (BMI), waist circumference, and waist-hip ratio. Waist circumference and waist-hip ratio are measures for central body fatness while BMI is a proxy for overall body fatness. This study revealed an obesity paradox among African-American men in our study population, where a high BMI and waist circumference associated with a decreased disease risk. Currently, our case-control study supports the aims of the DoD Impact award, W81XWH1810588 (PI Ambs), A Precision Medicine Study of How Inflammation May Underlie the Excessive Burden of Prostate Cancer in Men of African Ancestry, with the collected biospecimens and survey data.